Derivatized DTPA complexes pharmaceutical agents containing these compounds, their use, and processes for their production

ABSTRACT

Compounds of general Formula I ##STR1## wherein Z 1  and Z 2  in each case independently mean the residue 
     
         --(CH.sub.2).sub.m --(C.sub.6 H.sub.4).sub.q --(O).sub.k --(CH.sub.2).sub.n 
    
      --(C 6  H 4 ) l  --(O) r  --R, 
     wherein 
     m and n means the numbers 0-20, 
     k, l, q and r means the numbers 0 and 1, and 
     R means a hydrogen atom, an optionally OR 1  -substituted C 1  -C 6  -alkyl residue, or a CH 2  COOR 1  group with R 1  meaning a hydrogen atom, a C 1  -C 6  -alkyl residue, or a benzyl group, 
     with the proviso that at least two substituents X stand for a metal ion equivalent; that one of the substituents Z 1  and Z 2  stands for a hydrogen and the other is not H; that--if n and l each means the number 0--k and r do not simultaneously mean the number 1; that --(O) r  --R is not --OH; and that Z 1  and Z 2  are not --CH 2  --C 6  H 4  --O--CH 2  --COOCH 2  C 6  H 5  or --CH 2  --C 6  H 4  --O--(CH 2 ) 5  --COOCH 2  C 6  H 5 , are valuable pharmaceutical agents, e.g., for NMR or X-ray imaging.

This is a continuation of application Ser. No. 08/319,357, filed Oct. 6,1994, which is a continuation of Ser. No. 07/909,379, filed Jul. 6,1992, ABANDONED, which is a continuation of Ser. No. 07/809,803,ABANDONED, filed Dec. 20, 1991, which is a continuation of applicationSer. No. 07/780,840, filed Oct. 23, 1991, ABANDONED, which is acontinuation-in-part of application Ser. No. 07/544,530, filed Jun. 28,1990, ABANDONED, the disclosures of which are hereby incorporated byreference.

BACKGROUND OF THE INVENTION

The invention relates to novel complexes and complex salts, agentscontaining these compounds, their use in diagnostics and therapy, aswell as processes for preparing these compounds and agents.

Metallic complexes have been scrutinized as early as at the beginning ofthe fifties as contrast media for radiology. The compounds then employedwere, however, of such toxicity that utilization on human patients couldnot be considered. It was, therefore, entirely surprising to find thatcertain complex salts exhibit adequate compatibility for consideringroutine administration to human patients for diagnostic purposes. Thefirst representative of this class of compounds was the dimeglumine saltof Gd DTPA gadolinium(III) complex of diethylenetriaminepentaaceticacid! described in the European Patent Application, Publication No.71564, which proved itself very well in the form of a contrast mediumfor nuclear spin tomography. This compound has been registered, underthe name of "Magnevist", worldwide as the first NMR diagnostic agent.

Contrast media exhibiting an at least only partial extrarenal excretionwould be desirable, in particular for patients with limited kidneyfunction.

Consequently, there is a need for NMR contrast media exhibiting variouspharmacokinetic behaviors.

SUMMARY OF THE INVENTION

The invention makes such compounds and media available, and alsoprovides a process for their production.

The compounds according to this invention display renal elimination aswell as excretion with feces.

Surprisingly, elimination via the gallbladder, however, is not the onlyextrarenal path of elimination: in NMR studies on rats, upon intravenousadministration of the compounds of this invention, a contrastenhancement of the gastrointestinal tract has also been unexpectedlyobserved. The kidneys, as well as implanted tumors, are likewisevisualized with improved contrast.

The elimination (secretion) by way of the stomach has the advantage thatdemarcation of abdominal structures (e.g., the pancreas) from thegastrointestinal tract is made possible, with a simultaneous contrastenhancement of pathological processes (tumors, inflammations). Imagingof the renal system, of the liver and gallbladder, and the bile ductscan moreover likewise be achieved. Besides the improved visualization ofulcers and stomach carcinomas, it is also possible to perform studiesregarding gastric acid secretion with the aid of imaging procedures.

Accordingly, by making the compounds of this invention available, helpcan be extended to patients with renal insufficiency as well as patientssuffering from gastrointestinal disorders (at least 10% of thepopulation in the Western industrial countries). Most of these patients,as well as a large number of patients suspected of harboring suchdisease, must submit to diagnostic tests. At present, two methodssuitable for this purpose are utilized above all: Endoscopy and X-raydiagnostics with the aid of barium contrast media.

These tests exhibit various drawbacks: they carry the risk of radiationstress, cause trauma, are connected with inconvenience, occasionallyeven with risk to the patient, and thus can evoke psychological stress.In most instances, these tests must be repeated; their performance isrelatively complicated, require the patient's active cooperation (e.g.assumption of a specific bodily attitude) and frequently cannot beemployed in case of frail and high-risk patients.

Provision of novel diagnostic methods for the identification andlocalization of gastrointestinal diseases, which methods do not exhibitthese drawbacks, has thus likewise been attained by the complexcompounds and agents according to this invention.

Their pharmacokinetics permits, even without specific measures, animprovement in the diagnosis of numerous diseases. The complexes for themost part are excreted again in unchanged form and rapidly so that,especially also in case of using relatively toxic metallic ions, nodamaging effects are observed even at high dosage.

The practical use of the novel complexes is also facilitated by theirfavorable chemical stability.

The compounds of this invention are characterized by general Formula I##STR2## wherein Z¹ and Z² in each case independently mean the residue

    --(CH.sub.2).sub.m --(C.sub.6 H.sub.4).sub.q --(O).sub.k --(CH.sub.2).sub.n --(C.sub.6 H.sub.4).sub.l --(O).sub.r --R,

wherein

m and n means the numbers 0-20,

k, l, q and r means the numbers 0 and 1, and

R means a hydrogen atom, an optionally OR¹ -substituted C₁ -C₆ -alkylresidue, or a CH₂ COOR¹ group with R¹ meaning a hydrogen atom, a C₁ -C₆-alkyl residue, or a benzyl group,

X means a hydrogen atom and/or a metal ion equivalent of an element ofatomic numbers 21-29, 42, 44 or 57-83,

with the proviso that at least two substituents X stand for a metal ionequivalent; that one of the substituents Z¹ and Z² stands for a hydrogenatom and the other is not H; that--if n and l each means the number 0--kand r do not simultaneously mean the number 1, that --(O)_(r) --R is not--OH; and that Z¹ and Z² are not --CH₂ --C₆ H₄ --O--CH₂ --COOCH₂ C₆ H₅or --CH₂ --C₆ H₄ --O--(CH₂)₅ --COOCH₂ C₆ H₅, as well as their salts withinorganic and/or organic bases, amino acids or amino acid amides.

If the agent of this invention is intended for use in NMR diagnostics,then the central ion of the complex salt must be paramagnetic. Theseare, in particular, the divalent and trivalent ions of the elements ofatomic numbers 21-29, 42, 44 and 58-70. Suitable ions are, for example,the chromium(III), manganese(II), iron(II), cobalt(II), nickel(II),copper(II), praseodymium(III), neodymium(III), samarium(III) andytterbium(III) ions. On account of their very strong magnetic moment,the gadolinium(III), terbium(III), dysprosium(III), holmium(III),erbium(III) and iron(III) ions are especially preferred.

If the agent of this invention is meant for X-ray diagnostics, then thecentral ion must be derived from an element of a higher atomic number inorder to obtain adequate absorption of the X-rays. It has been foundthat suitable diagnostic media for this purpose are those containing aphysiologically compatible complex salt with central ions of elements ofatomic numbers between 21-29, 42, 44, 57-83; these are, for example, thelanthanum(III) ion and the above-cited ions of the lanthanide series.

The numbers standing for m and n are preferably 0 to 5.

Suitable as the alkyl substituents R and R¹ are straight-chain orbranched hydrocarbons of up to 6, preferably up to 4 carbon atoms which,in case of R, are optionally substituted by one or several, preferably1-3, hydroxy or C₁ -C₆ -, preferably C₁ -C₄ -alkoxy groups.

Examples that can be cited for optionally substituted alkyl groups arethe methyl, hydroxymethyl, ethyl, 2-hydroxyethyl,2-hydroxy-1-(hydroxymethyl)ethyl, 1-(hydroxymethyl)ethyl, propyl,isopropyl, 2- and 3-hydroxypropyl, 2,3-dihydroxypropyl, n-, sec- andtert-butyl, 2-, 3- and 4-hydroxybutyl, 2- and 3-hydroxyisobutyl, pentyl,2-, 3- and 4-hydroxy-2-methylbutyl, 2,3,4-trihydroxybutyl,1,2,4-trihydroxybutyl, cyclopentyl, cyclohexyl,2,3,4,5,6-pentahydroxyhexyl groups as well as--in case of thehydroxyalkyl groups--their C₁ -C₆ -, preferably C₁ -C₄ -alkylderivatives, i.e., the corresponding C₁ -C₆ -alkoxy groups.

Preferred substituents Z¹ and Z² are the CH₂ --C₆ H₄ --OCH₃, --CH₂ --C₆H₅, --CH₂ --C₆ H₄ --O--CH₂ --C₆ H₄ --OCH₃, --CH₂ --O--CH₂ --C₆ H₅, --CH₂--C₆ H₄ --O--CH₂ --COOH, --CH₂ --C₆ H₄ --OC₂ H₅, --CH₂ --C₆ H₄ --OC₄ H₉,--CH₂ --C₆ H₄ --O--CH₂ --C₆ H₅ residues. Thus, m preferably is l, and/orq preferably is l, k and/or r preferably is l, etc., and two phenylrings are preferably separated by --O--CH₂, etc.

In case not all of the acidic hydrogen atoms are substituted by thecentral ion, it is possible to replace one, several, or all remaininghydrogen atom(s) by cations of inorganic and/or organic bases or aminoacids. Suitable inorganic cations are, for example, the lithium ion, thepotassium ion, the calcium ion, the magnesium ion and, in particular,the sodium ion. Suitable cations of organic bases are, inter alia, thoseof primary, secondary or tertiary amines, such as, for example,ethanolamine, diethanolamine, morpholine, glucamine,N,N-dimethylglucamine and, in particular, N-methylglucamine. Suitablecations of amino acids are, for example, those of lysine, of arginine,and or ornithine. Suitable cations of amino acid amides are lysinemethyl amide, glycine ethyl amide and serine methylamide.

The production of the complex compounds of this invention in accordancewith general Formula I takes place by converting, in a manner known perse, compounds of general Formula II ##STR3## wherein R² means an acidblocking group,

Z³ and Z⁴ each means a hydrogen atom or the residue --(CH₂)_(m) --(C₆H₄)_(q) --OH, with the proviso that one of the substituents Z³ and Z⁴ isa hydrogen atom and the other is the indicated residue, and m and q areas in Formula I

into a compound with the residue indicated for Z¹ and Z², splitting offthe acid blocking groups R², reacting the thus-obtained complex-formingacids of general Formula I where X is a hydrogen atom (Formula I') withat least one metal oxide or metal salt of an element of atomic numbers21-29, 42, 44 or 57-83, and subsequently --if desired--substituting anypresent acidic hydrogen atoms by cations of inorganic and/or organicbases, amino acids or amino acid amides.

Suitable acid blocking groups R² are lower alkyl, aryl and aralkylgroups, e.g. the methyl, ethyl, propyl, n-butyl, tert-butyl, phenyl,benzyl, diphenylmethyl, triphenylmethyl, bis(p-nitrophenyl)methylgroups, as well as trialkylsilyl groups.

Splitting off of the blocking groups R² takes place according to methodsknown to one skilled in the art for example, E. Wunsch, "Methoden derOrg. Chemie" Methods of Organic Chemistry! (Houben-Weyl), vol. XV/1, 4thed., 1974, pp. 315 et seq.!, for instance by hydrolysis, hydrogenolysisor alkaline saponification of the esters with an alkali inaqueous-alcoholic solution at temperatures of 0°-50° C. Organic orinorganic acids are used for splitting off the tert-butyl esters whichare especially advantageous for the present reactions: The estercompound dissolved in a suitable anhydrous organic solvent, butpreferably the pulverized dry material, is combined either with ahydrogen halide solution in glacial acetic acid, with trifluoroaceticacid, or also with boron trifluoride diethyl etherate in glacial aceticacid and split off at temperatures of -10° C. to 60° C., preferably atroom temperature.

The compounds of general Formula II, serving as educts for theproduction of the complex compounds of this invention, are known (DOS3,710,730 and literature cited therein) or can be synthesizedanalogously to the preparation directions described therein. The entiredisclosure of U.S. Ser. No. 07/430,442 (corresponding to the mentionedDOS), of Oct. 2, 1989, is hereby incorporated by reference herein.

A series of literature methods known to a person skilled in the art isavailable for reacting the known aliphatic or aromatic hydroxy compoundsto the corresponding arylalkyl or dialkyl ethers (for example, J. March,Advanced Organic Chemistry, 3rd ed., 1985, pp. 342 et seq.).

For this purpose, the compounds of Formula II wherein R² stands for analkali-stable acid blocking group are dissolved in a polar aproticsolvent, such as, for example, tetrahydrofuran, dimethoxyethane ordimethyl sulfoxide, and combined with a base, such as, for example,sodium hydride, sodium hydroxide or alkali or alkaline earth carbonates,at temperatures of between -30° C. and the boiling point of therespective solvent, but preferably between 0° C. and 60° C.

A compound of general Formula III is added to this mixture

    Y--(CH.sub.2).sub.n --(C.sub.6 H.sub.4).sub.l --(O).sub.r --R (III)

wherein Y means a nucleofugal entity, such as, for example, Cl, Br, I,CH₃ --C₆ H₄ SO₃ or CF₃ SO₃, and the remaining indices have the samemeanings as in general Formula I.

The reaction periods are 30 minutes to 8 hours, depending on the sterichindrance of the residues participating in the reaction.

As an alternative to the aforedescribed reaction conditions, it ispossible to produce aryl-alkyl as well as dialkyl ethers in a veryadvantageous way by phase transfer catalysis (Starks and Liotta, PhaseTransfer Catalysis, Academic Press, N.Y. 1978, pp. 128-138).

For this purpose, the reaction is performed in a two-phase mixture of anaqueous base, preferably 30% sodium hydroxide solution, and awater-immiscible organic aprotic solvent. Suitable phase transfercatalysts are the compounds known to a person skilled in the art, butpreferably tetraalkylammonium or tetralkylphosphonium salts.

If it is desired to synthesize compounds of general Formula I wherein k,n, l and r=0 and R means a hydrogen atom, then it is possible to conductthe synthesis in analogy to the methods known from the literature,starting with the corresponding unsubstituted amino acid (e.g.phenylalanine).

However, if a series of analogous compounds is to be synthesized, thenit is recommended to prepare the phenol derivatives described in DOS3,710,730 and to reductively remove the phenol function in accordancewith literature methods known to those skilled in the art. Above all,the reduction of aryl diethyl phosphates with titanium can be citedwhich can be performed in a very advantageous way also in the presenceof ester groups S. C. Welch et al., J. Org. Chem. 43: 4797-99 (1978) andliterature cited therein!. In this procedure, the corresponding aryldiethyl phosphate is first formed from the phenolic educt by reactionwith phosphoric acid diethyl ester chloride in a 70-100% yield,preferably by the use of sodium hydride as the base in a polar apropticsolvent. Subsequently, the reduction is performed with freshly preparedtitanium metal. Preferably, anhydrous titanium(III) chloride is reducedby magnesium or potassium in anhydrous tetrahydrofuran under an inertgas for preparing highly active titanium.

The above-described diethyl phosphate is added to such a mixture andheated under reflux for 2-24 hours, preferably 6-16 hours. After thereaction is terminated, the mixture is optionally worked up bychromatography. It is also possible to employ the palladium-catalyzedreduction of the corresponding aryl triflates according to S. Cacchi etal., Tetr. Lett. 27: 5541-44 (1986).

The thus-obtained compounds of general Formula I' wherein X means ahydrogen atom represent complexing agents. They can be isolated andpurified or can be converted, without isolation, into metal complexes ofgeneral Formula I with at least two of the substituents X meaning ametal ion equivalent.

The metal complexes of this invention can be produced in a way disclosedin Patent DE 3,401,052, by dissolving or suspending the metal oxide or ametal salt (e.g. the nitrate, acetate, carbonate, chloride or sulfate)of the element of atoms numbers 21-29, 42, 44 or 58-70 in water and/or alower alcohol (such as methanol, ethanol or isopropanol) and reactingwith a solution or suspension of the equivalent amount of thecomplex-forming acid of general Formula I' wherein X means a hydrogenatom, preferably at temperatures of between 40° and 100° C., andsubsequently--if desired--substituting any present acidic hydrogen atomsof acid groups by cations of inorganic and/or organic bases, amino acidsor amino acid amides.

Neutralization is herein effected with the aid of inorganic bases (forexample, hydroxides, carbonates or bicarbonates) of, for example,sodium, potassium, lithium, magnesium or calcium and/or with the aid ororganic bases, such as, inter alia, primary, secondary and tertiaryamines, e.g. ethanolamine, morpholine, glucamine, N-methyl- andN,N-dimethyl-glucamine, as well as basic amino acids, such as, forexample, lysine, arginine and ornithine.

In order to prepare the neutral complex compounds, it is possible, forexample, to add to the acidic complex salts in an aqueous solution orsuspension such an amount of the desired bases that the neutral point isreached. The resultant solution can subsequently be evaporated todryness under vacuum. It is frequently advantageous to precipitate thethus-formed neutral salts by adding water-miscible solvents, such as,for example, lower alcohols (methanol, ethanol, isopropanol, andothers), lower ketones (acetone and others), polar ethers(tetrahydrofuran, dioxane, 1,2-dimethoxyethane, and others), and toobtain in this way crystallized products which can be readily isolatedand easily purified. It proved to be especially advantageous to add thedesired base as early as during the complexing to the reaction mixture,thereby saving a process step.

If the acidic complex compounds contain several free acidic groups, thenit is frequently expedient to prepare neutral mixed salts containinginorganic as well as organic cations as the counterions.

This can be done, for example, by reacting the complexing acid in anaqueous suspension or solution with the oxide or salt of the elementyielding the central ion and with half the amount of an organic baseneeded for neutralization, isolating the thus-formed complex salts,purifying same if desired, and then combining same for completeneutralization with the required amount of inorganic base. The sequenceof adding the bases can also be reversed.

The pharmaceuticals of this invention can be prepared in a likewiseconventional way by suspending or dissolving the complex compoundsaccording to the invention--optionally adding the additives customary ingalenic pharmacy--in an aqueous medium and then optionally sterilizingthe suspension or solution. Suitable additives are, for example,physiologically acceptable buffers (e.g. tromethamine), small additionsof complexing agents (such as, for example,diethylene-triaminepentaacetic acid) or, if necessary, electrolytes(such as, for example, sodium chloride) or, if necessary, antioxidants,e.g. ascorbic acid.

If, for enteral administration or other purposes, suspensions orsolutions of the agents of this invention in water or a physiologicalsaline solution are desirable, they are mixed with one or severalauxiliary agent(s) customary in galenic pharmacy (for examplemethylcellulose, lactose, mannitol) and/or tenside(s), e.g. lecithins,"Tween", "Myrj" and/or flavoring substance(s) for taste improvement(e.g. ethereal oils).

In principle, it is also possible to prepare the pharmaceuticals of thisinvention even without isolation of the complex salts. In any event,special care must be directed toward effecting the chelate formation sothat the salts and salt solutions according to this invention arepractically devoid of toxically active metal ions that are notcomplexed.

This can be ensured, for example, with the aid of color indicators, suchas xylenol orange, by control titrations during the manufacturingprocess. Consequently, the invention also relates to processes forpreparing the complex compounds and their salts. The final safetyfeature resides in purification of the isolated complex salt.

The pharmaceutical agents of this invention can be administered tomammals, including humans, in a dose of 1 μmol/kg to 5 mmol/kg,preferably 10 μmol to 0.5 mmol/kg of the complex salt according to theinvention. For intravenous injection, aqueous formulations are utilizedwith a concentration of 50 μmol/l to 2 mol/l, preferably 100 mmol/l to 1mol/l. Rectal as well as oral administration is preferably performedwith solutions of a concentration of 0.1 mmol/l to 100 mmol/l. Thevolumes administered are between 5 ml and 2 l, depending on thediagnostic problem.

The agents according to this invention meet the variegated prerequisitesfor suitability as contrast media. Thus, they are excellently suited,upon enteral or parenteral administration, to improve the informationcontent of the image obtained with the aid of the NMR tomograph, byincreasing the signal intensity. They show furthermore the high efficacynecessary for burdening the body with minimum amounts of foreignsubstances, and the good compatibility required for maintaining thenon-invasive character of the tests.

The high water solubility and low osmolality of the agents according tothis invention permits the production of highly concentrated solutionsso that the volume load on the circulation is maintained withintolerable limits and dilution by body fluids is compensated.Furthermore, the agents of this invention exhibit not only a highstability in vitro but also a surprisingly high stability in vivo sothat release or exchange of the--actually toxic--ions not covalentlybound in the complexes takes place only extremely gradually within thetime wherein the novel contrast media are again entirely eliminated.

The agents of this invention can also be utilized for radiation therapy.Thus, complexes of gadolinium are excellently suited due to the largecapture cross section for neutron capture therapy. If the agent of thisinvention is intended for use in the version of radiation therapyproposed by R. L. Mills et al. Nature, 336: 787 (1988)!, then thecentral ion must be derived from a Mossbauer isotope, such as, forexample, ⁵⁷ Fe or ¹⁵¹ Eu.

When administered, the agents of this invention can also be giventogether with a suitable carrier, such as, for example, serum orphysiological saline solution and/or together with a protein, such as,for example, human serum albumin. The dosage herein is dependent on thetype of cellular disorder and on the properties of the metal complexutilized.

In certain aspects, this invention can exclude compounds andcompositions wherein Z¹ is phenyl and Z² is H and aspects wherein, when--(O)_(r) --R is alkoxy, k, l, and q are simultaneously zero.

Without further elaboration, it is believed that one skilled in the artcan, using the preceding description, utilize the present invention toits fullest extent. The following preferred specific embodiments are,therefore, to be construed as merely illustrative, and not limitative ofthe remainder of the disclosure in any way whatsoever.

In the foregoing and in the following examples, all temperatures are setforth uncorrected in degrees Celsius and unless otherwise indicated, allparts and percentages are by weight.

The entire disclosure of all applications, patents and publications, ifany, cited above and below, and of corresponding application FederalRepublic of Germany P 39 22 005.2, filed Jun. 30, 1989, are herebyincorporated by reference.

EXAMPLE 1 (a)3,6,9-Triaza-3,6,9-tris(tert-butyoxycarbonylmethyl)-4-(4-methoxybenzyl)undecanedioic Acid Di-tert-butyl Diester

At 0° C. 1.56 g (2 millimoles) of3,6,9-triaza-3,6,9-tris(tert-butyoxycarbonylmethyl)-4-(4-hydroxybenzyl)undecanedioic acid di-tert-butyl diester (Example 9f of DOS 3,710,730)is combined in tetra-hydrofuran with 66 mg (2.2 mmol) of 80% strengthsodium hydride. This mixture is combined with 0.31 g (2.2 mmol) ofiodomethane and stirred for 30 minutes. Then the solution is combinedwith water, tetrahydrofuran is removed by distillation, and the aqueousemulsion is extracted with diethyl ether. The organic phase is washedwith water, dried over Na₂ SO₄, and concentrated.

Yield: 1.55 g (97.6%)

Calculated: C 63.53 H 9.01 N 5.29 Found: C 63.37 H 8.96 N 5.32

(b)3,6,9-Triaza-3,6,9-tris(carboxymethyl)-4-(4-methoxybenzyl)undecanedioicAcid

1.27 g (1.6 mmol) of the tert-butyl ester described in Example 1(a) isdissolved in 25 ml of trifluoroacetic acid and stirred for one hour atroom temperature. The solution is then combined with diethyl ether, theprecipitate is suctioned off, washed with ether and dried at 40° C.under vacuum over phosphorus pentoxide. The crude product is dissolvedin water and combined under agitation with active carbon. The mixture isfiltered off from the carbon and lyophilized three times to removeresidual trifluoroacetic acid.

Yield: 0.62 g (75.4%) Calculated: C 51.46 H 6.09 N 8.18 Found: C 51.27 H6.02 N 8.11

(c) Gadolinium Complex of3,6,9-Triaza-3,6,9-tris-(carboxymethyl)-4-(4-methoxybenzyl)undecanedioicAcid

513 mg (1 mmol) of the complexing acid described in Example 1(b) isdissolved in about 30 ml of water and combined at 80° C. with 181 mg(0.5 mmol) of Gd₂ O₃. After 30 minutes, the almost clear solution isfiltered and the filtrate freeze-dried.

Yield: 649 mg (97.2%) based on the anhydrous material Calculated: C39.57 H 4.23 N 6.29 Gd 23.55 Found: C 39.47 H 4.29 N 6.21 Gd 23.19

Disodium Salt of the Gadolinium Complex

The complex (500 mg, 0.75 mmol) obtained as described above is dissolvedin 10 times the amount of water and combined by means of a microburettewith 1.5 ml of a 1N sodium hydroxide solution.

After freeze-drying, 533 mg of white crystals is obtained.

T₁ relaxation (1/mmol·sec) is

in water 4.54±0.13

in plasma 6.89±0.17

Di-N-methyl-D-glucamine Salt of the Gadolinium Complex

3.34 g (5 mmol) of the gadolinium complex is combined in 40 ml of waterin portions with 1.96 g (10 mmol) of N-methyl-D-glucamine underagitation. After the base has been completely dissolved, the product isfreeze-dried. There remains 5.55 g of a colorless crystalline compound.

H₂ O content (Karl Fischer determination): 4.73%

(d) Europium Complex of3,6,9-Triaza-3,6,9-tris-(carboxymethyl)-4-(4-methoxybenzyl)undecanedioicAcid

5.13 g (10 mmol) of the complexing acid described in Example 1(b) isdissolved in about 30 ml of water and combined at 80° C. with 1.76 g (5mmol) of Eu₂ O₃. After 30 minutes, the almost clear solution is filteredand the filtrate freeze-dried.

Yield: 6.62 g Analysis (based on anhydrous substance) Calculated: C39.89 H 4.26 N 6.34 Eu 22.94 Found: C 39.71 H 4.38 N 6.17 Eu 22.58

Disodium Salt of the Europium Complex

The complex described above (497 mg, 0.75 mmol) is dissolved in 10 timesthe quantity of water and combined by means of a microburette with 1.5ml of a 1N sodium hydroxide solution. After freeze-drying, 540 mg ofwhite crystals is obtained.

Di-N-methyl-D-glucamine Salt of the Europium Complex

3.31 g (5 mmol) of the europium complex is mixed in 40 ml of water inportions with 1.96 g (10 mmol) of N-methyl-D-glucamine under agitation.After the base has been completely dissolved, the mixture isfreeze-dried. There remains 5.63 g of a colorless, crystalline compound.

(e) Iron(III) Complex of3,6,9-Triaza-3,6,9-tris-(carboxymethyl)-4-(4-methoxybenzyl)undecanedioicAcid

5.13 g (10 mmol) of the complexing acid disclosed in Example 1(b) isdissolved in about 30 ml of water and combined at 80° C. with 798 mg (5mmol) of Fe₂ O₃. After 30 minutes, the almost clear solution is filteredand the filtrate freeze-dried.

Yield: 5.66 g Analysis (based on anhydrous substance): Calculated: C46.66 H 4.98 N 7.42 Fe 9.86 Found: C 46.71 H 5.03 N 7.38 Fe 9.81

Disodium Salt of the Iron(III) Complex

The complex obtained as described above (425 mg, 0.75 mmol) is dissolvedin 10 times the amount of water and combined by means of a microburettewith 1.5 ml of a 1N sodium hydroxide solution. After freeze-drying, 460mg of white crystals is obtained.

Di-N-methyl-D-glucamine Salt of the Iron(III) Complex

2.83 g (5 mmol) of the iron(III) complex is combined in 40 ml of waterin portions with 1.96 g (10 mmol) of N-methyl-D-glucamine underagitation. After the base has been completely dissolved, the solution isfreeze-dried. There remains 4.83 g of a colorless, crystalline compound.

Analogously, with bismuth oxide, Bi₂ O₃, the bismuth complex is obtainedas the disodium salt and, respectively, as the di-N-methyl-D-glucaminesalt.

Example 2 (a)3,6,9-Triaza-3,6,9-tris(tert-butoxycarbonylmethyl)-5-(4-methoxybenzyl)undecanedioicAcid Di-tert-butyl Ester

In accordance with the directions given in Example 1(a), 3.9 g (5 mmol)of3,6,9-triaza-3,6,9-tris-(tert-butoxycarbonylmethyl)-5-(4-hydroxybenzyl)undecanedioicacid di-tert-butyl ester (Example 17d in DOS 3,710,730) is reacted to3.61 g (91% of theory) of the title compound.

Calculated: C 63.53 H 9.01 N 5.29 Found: C 63.59 H 9.07 N 5.27

(b)3,6,9-Triaza-3,6,9-tris(carboxymethyl)-5-(4-methoxybenzyl)undecanedioicAcid

3.18 g (4 mmol) of the tert-butyl ester described in Example 2(a) istreated in accordance with the directions set forth in Example 1(b) withtrifluoroacetic acid and worked up, thus obtaining 1.62 g (79% oftheory) of a colorless lyophilized product.

Calculated: C 51.46 H 6.09 N 8.18 Found: C 51.34 H 6.14 N 8.11

(c) Gadolinium Complex of3,6,9-Triaza-3,6,9-tris-(carboxymethyl)-5-(4-methoxybenzyl)undecanedioicAcid

According to the directions in Example 1(c), 1.03 g (2 mmol) of thecomplex-forming acid described in Example 2(b) is complexed with Gd₂ O₃,yielding 1.32 g (99% of theory) of a colorless lyophilized product.

Calculated: C 39.57 H 4.23 N 6.29 Gd 23.55 Found: C 39.51 H 4.19 N 6.25Gd 23.61

The T₁ relaxation (1/mmol·sec) is

in water 4.17±0.14

in plasma 6.61±0.18

Example 3 (a) 3,6,9-Triaza-3,6,9-tris(tert-butoxycarbonylmethyl)-4-4-(4-methoxybenzyloxy)benzyl!undecanedioic Acid Di-tert-butyl Ester

At 0° C., 1.56 g (2 mmol) of3,6,9-triaza-3,6,9-tris(tert-butoxycarbonylmethyl)-4-(4-hydroxybenzyl)undecanedioicacid di-tert-butyl ester (Example 9f of DOS 3,710,730) is combined intetrahydrofuran with 66 mg (2.2 mmol) of 80% strength sodium hydride. Tothis mixture is added 0.3 ml (2.2 mmol) of 4-methoxybenzyl chloride andthe mixture is stirred overnight. The solution is then combined withwater, tetrahydrofuran is removed by distillation, and the aqueousemulsion is extracted with diethyl ether. The organic phase is washedwith water, dried over Na₂ SO₄, and concentrated. The resultantcolorless oil is chromatographed on silica gel (ether/hexane 1:1).

Yield: 1.17 g (65% of theory) of a colorless oil. Calculated: C 65.38 H8.62 N 4.67 Found: C 65.29 H 8.65 N 4.59

(b) 3,6,9-Triaza-3,6,9-tris(carboxymethyl)-4-4-(4-methoxybenzyloxy)benzyl!undecanedioic Acid

1.80 g (2 mmol) of the tert-butyl ester set forth in Example 3(a) istreated analogously to the directions given in Example 1(b) withtrifluoroacetic acid and reacted to 905 mg (73% of theory) of colorless,flaky lyophilized product.

Calculated: C 56.21 H 6.02 N 6.78 Found: C 56.10 H 5.98 N 6.82

(c) Gadolinium Complex of 3,6,9-Triaza-3,6,9-tris-(carboxymethyl)-4-4-(4-methoxybenzyloxy)benzyl!-undecanedioic Acid

Analogously to the directions given for Example 1(c), 620 mg (1 mmol) ofthe complexing acid described in Example 3(b) is complexed and workedup, yielding 758 mg (98% of theory).

Calculated: C 45.01 H 4.43 N 5.43 Gd 20.32 Found: C 44.93 H 4.49 N 5.37Gd⁻ 20.18

The T₁ relaxation (1/mmol·sec) amounts to

in water 4.23±0.16

in plasma 6.99±0.13

Example 4 (a) Diethyl Phosphate of3,6,9-Triaza-3,6,9-tris-(tert-butoxycarbonylmethyl)-4-(4-hydroxybenzyl)undecanedioicAcid Di-tert-butyl Ester

11.2 g (14.36 mmol) of the phenol disclosed in DOS 3,710,730 (Example9f) is dissolved in 100 ml of absolute tetrahydrofuran (THF). To thismixture is added 380 mg (15.8 mmol) of sodium hydride (prepared from 50%NaH in paraffin oil by washing three times with 10 ml of THF). After 30minutes at room temperature, 2.60 g (15.0 mmol) of phosphoric aciddiethyl ester chloride is added and the mixture stirred for 24 hours atroom temperature.

The solution is diluted with 500 ml of ether and washed three times with300 ml of 10% sodium hydroxide solution. After drying the organic phaseover magnesium sulfate, the product is concentrated under vacuum and theresidue purified by flash chromatography (eluent: ether/hexane=1:1).

Yield: 11.97 g (91% of theory) of a pale-yellow oil. Calculated: C 59.00H 8.58 N 4.59 P 3.38 Found: C 58.88 H 8.63 N 4.63 P 3.30

(b)3,6,9-Triaza-3,6,9-tris(tert-butoxycarbonylmethyl)-4-benzylundecanedioicAcid Di-tert-butyl Ester

A mixture of 1.33 g (8.62 mmol) of anhydrous titanium(III) chloride and1.02 g (26.09 mmol) of finely chopped potassium in 20 ml oftetrahydrofuran is heated under reflux in an argon atmosphere for onehour.

Within 15 minutes, a solution of 11.5 g (12.55 mmol) of the compounddescribed in Example 4(a) in 50 ml of tetrahydrofuran is added dropwiseto this mixture. Then the mixture is heated under reflux for 8 hours,cooled in an ice bath, 20 ml of methanol is gently added, then 100 ml ofwater is added, and the mixture is extracted three times with 200 ml ofether. The organic phases are dried over magnesium sulfate andconcentrated under vacuum. The residue is chromatographed on silica gel(eluent: hexane/ether=2:1), thus obtaining 8.9 g (93% of theory) of thetitle compound as a colorless oil which crystallizes upon standing.

Calculated: C 64.46 H 9.10 N 5.50 Found: C 64.54 H 9.15 N 5.41

(c) 3,6,9-Triaza-3,6,9-tris(carboxymethyl)-4-benzylundecanedioic Acid

Analogously to the directions set forth in Example 1(b), 7.64 g (10mmol) of the tert-butyl ester described in Example 4(b) is reacted to4.01 g (83% of theory) of the title compound.

Calculated: C 52.17 H 6.05 N 8.69 Found: C 52.23 H 5.99 N 8.73

(d) Gadolinium Complex of3,6,9-Triaza-3,6,9-tris-(carboxymethyl)-4-benzylundecanedioic Acid

2.42 g (5 mmol) of the complex-forming acid described in Example 4(c) isreacted analogously to the directions given in Example 1(c) to 3.14 g(98.5% of theory) of the title compound, obtaining the gadoliniumcomplex as a colorless, flaky lyophilized product.

Calculated: C 39.55 H 4.11 N 6.59 Gd 24.66 Found: C 39.47 H 4.19 N 6.52Gd 24.88

The T₁ relaxation (1/mmol·sec) is

in water 4.54±0.13

in plasma 6.89±0.17

Ytterbium Complex of3,6,9-Tris-3,6,9-tris(carboxymethyl)-4-benzylundecanedioic Acid

Analogously to the directions for preparing the gadolinium complex, thecorresponding ytterbium complex is obtained by using Yb₂ O₃ in place ofGd₂ O₃.

Example 5 (a)3,6,9-Triaza-3,6,9-tris(tert-butoxycarbonylmethyl)-4-benzyloxymethylundecanedioicAcid Di-tert-butyl Ester

Within 30 minutes, 7.2 ml (60 mmol) of benzyl bromide is added dropwiseat room temperature to a thoroughly stirred suspension of 14.1 g (20mmol) of4-hydroxymethyl-3,6,9-triaza-3,6,9-tris(tert-butoxycarbonylmethyl)undecanedioicdi-tert-butyl diester described in DOS 3,710,730 (Example 37d) and 0.3 gof tetrabutylammonium hydrogen sulfate in 200 ml of dichloromethane/200ml of 30% strength sodium hydroxide solution, and the mixture is thenagitated for 8 hours.

400 ml of water is added to this suspension; the organic phase isseparated and the aqueous phase extracted twice with respectively 150 mlof dichloromethane. After drying the combined organic phases overmagnesium sulfate, the product is chromatographed on silica gel(ether/hexane=1:1), thus obtaining 13.0 g (82% of theory) of the titlecompound as a colorless oil.

Calculated: C 63.53 H 9.01 N 5.29 Found: C 63.42 H 9.07 N 5.21

(b)3,6,9-Triaza-3,6,9-tris(carboxymethyl)-4-benzyloxymethylundecanedioicAcid

Analogously to the directions given for Example 1(b), 7.94 g (10 mmol)of the tert-butyl ester set forth in Example 5(a) is reacted withtrifluoroacetic acid to 4.06 g (79% of theory) of the title compound.

Calculated: C 51.46 H 6.09 N 8.18 Found: C 51.51 H 6.06 N 8.12

(c) Gadolinium Complex of3,6,9-Triaza-3,6,9-tris-(carboxymethyl)-4-benzyloxymethylundecanedioicAcid

In analogy to the directions in Example 1(c), 2.57 g (5 mmol) of thecomplexing acid described in Example 5(b) is reacted to 3.30 g (98.9% oftheory) of the title compound, yielding a colorless, flaky solid.

Calculated: C 39.57 H 4.23 N 6.29 Gd 23.55 Found: C 39.51 H 4.26 N 6.35Gd 23.27

The T₁ relaxation (1/mmol·sec) is

in water 4.39±0.12

in plasma 6.31±0.15

Example 6 (a)3,6,9-Triaza-3,6,9-tris(tert-butoxycarbonylmethyl)-4-(4-carboxymethoxybenzyl)undecanedioicAcid Bis(tert-butyl) Ester

At 0° C., 23.40 g (30 mmol) of3,6,9-triaza-3,6,9-tris(tert-butoxycarbonylmethyl)-4-(4-hydroxybenzyl)undecanedioicacid di-tert-butyl ester (Example 9f of DOS 3,710,730) is combined intetrahydrofuran with 2.7 g (90 mmol) of 80% strength sodium hydride. Tothis mixture is dropped 6.25 g (45 mmol) of bromoacetic acid intetrahydrofuran, and the mixture is stirred for one hour at 0° C. andovernight at room temperature.

The solution is then combined with water, tetrahydrofuran is removed bydistillation, and the aqueous phase is extracted with ethyl acetate. Theorganic phase is dried over sodium sulfate and concentrated.

The residue is chromatographed on silica gel in an eluent mixture ofdioxane/methanol/triethylamine (15:4:1); the combined fractions areconcentrated and divided between ethyl acetate and 1N citric acid. Theorganic phase is then dried over sodium sulfate and concentrated, thusobtaining 21.8 g (87% of theory) as a colorless oil.

Calculated: C 61.63 H 8.54 N 5.01 Found: C 61.62 H 8.62 N 4.95

(b)3,6,9-Triaza-3,6,9-tris(carboxymethyl)-4-(4-carboxymethoxybenzyl)undecanedioicAcid

Analogously to the directions given for Example 1(b), 21.0 g (25 mmol)of the tert-butyl ester described in Example 6(a) is reacted to 11.0 g(78.9% of theory) of the title compound.

Calculated: C 49.55 H 5.60 N 7.54 Found: C 49.31 H 5.51 N 7.47

(c) Gadolinium Complex of3,6,9-Triaza-3,6,9-tris-(carboxymethyl)-4-(4-carboxymethoxybenzyl)-undecanedioicAcid

5.57 g (10 mmol) of the complex-forming acid described in Example 6(b)is reacted analogously to the directions set forth in Example 1(c) toyield 7.01 g (98.5% of theory) of the title compound.

Calculated: C 38.81 H 3.96 N 5.90 Gd 22.09 Found: C 38.75 H 3.89 N 5.97Gd 21.93

The T₁ relaxation (1/mmol·sec) is

in water 5.00±0.01

in plasma 7.10±0.08

Example 7

Preparation of a Solution of the Sodium Salt of the Gadolinium(III)Complex of3,6,9-Triaza-3,6,9-tris-(carboxymethyl)-4-benzyloxymethylundecanedioicAcid

6.68 g (10 mmol) of the gadolinium complex obtained according to Example5(c) is dissolved in 70 ml of water pro injections (p.i.) and combineddropwise with 1N sodium hydroxide solution until a pH of 7.2 has beenreached. After adding 0.02 g of tromethamine, the mixture is filled upto 100 ml with water p.i.; the solution is dispensed into bottles andheat-sterilized.

Example 8 (a)3,6,9-Triaza-3,6,9-tris(tert-butoxycarbonylmethyl)-4-(4-ethoxybenzyl)undecanedioicAcid Di-tert-butyl Diester

At 0° C., 5.85 g (7.5 mmol) of3,6,9-triaza-3,6,9-tris(tert-butoxycarbonylmethyl)-4-(4-hydroxybenzyl)undecanedioicacid di-tert-butyl diester (Example 9f of DOS 3,710,730) is combined in100 ml of tetrahydrofuran with 0.30 g (10 mmol) of 801 strength sodiumhydride. To this mixture is added 1.56 g (10 mmol) of iodoethane and themixture is stirred for 3 hours. Then the solution is combined withwater, tetrahydrofuran is distilled off, and the aqueous emulsion isextracted with diethyl ether. The crude product obtained after dryingover sodium sulfate and concentration of the solvent is chromatographedon silica gel (system: hexane/ether/triethylamine 70:30:5).

Yield: 4.0 g (66%) Analysis (based on anhydrous material): Calculated: C63.91 H 9.11 N 5.20 Found: C 63.67 H 9.05 N 5.28

(b)3,6,9-Triaza-3,6,9-tris(carboxymethyl)-4-(4-ethoxybenzyl)undecanedioicAcid

3.64 g (4.5 mmol) of the tert-butyl ester disclosed in Example (8(a) isdissolved in 25 ml of trifluoroacetic acid, stirred for one hour at roomtemperature, and worked up analogously to Example 1(b).

Yield: 1.2 g (50.6%) Analysis (based on anhydrous substance):Calculated: C 52.36 H 6.13 N 7.97 Found: C 52.21 H 6.39 N 7.84

(c) Disodium Salt of the Gadolinium Complex of3,6,9-Triaza-3,6,9-tris(carboxymethyl)-4-(4-ethoxybenzyl)undecanedioicAcid

528 mg (1 mmol) of the complex-forming acid described in the precedingexample is dissolved in 40 ml of water and complexed at 80° C. with 181mg (0.5 mmol) of Gd₂ O₃. Then the mixture is neutralized with 2 ml of 1NNaOH, stirred with activated carbon, filtered, and the filtrate isfreeze-dried.

Yield: 700 mg (96.5%) Analysis (based on anhydrous material):Calculated: C 38.06 H 3.89 Gd 21.67 N 5.79 Na 6.34 Found: C 37.91 H 3.99Gd 21.30 N 5.69 Na 6.57

The T₁ relaxation (1/mmol·sec) is

in water 5.33±0.13

in plasma 8.69±0.53

Analogously, the corresponding europium complex is obtained witheuropium oxide, Eu₂ O₃.

Calculated: C 38.34 H 3.92 Eu 21.09 N 5.83 Na 6.38 Found: C 38.20 H 4.01Eu 20.87 N 5.79 Na 6.49

With iron oxide, Fe₂ O₃, the corresponding iron complex is obtainedanalogously:

Calculated: C 44.25 H 4.52 Fe 8.95 N 6.73 Na 7.37 Found: C 44.17 H 4.59Fe 8.52 N 6.81 Na 7.49

Example 9 (a)3,6,9-Triaza-3,6,9-tris(tert-butoxycarbonylmethyl)-4-(4-butoxybenzyl)undecanedioicAcid Di-tert-butyl Diester

Analogously to Example 8(a), 5.85 g (7.5 mmol) of3,6,9-triaza-3,6,9-tris(tert-butoxycarbonylmethyl)-4-(4-hydroxybenzyl)undecanedioicacid di-tert-butyl diester (Example 9f of DOS 3,710,730) is reacted with1.84 g (10 mmol) of 1-iodobutane and worked up as described therein.

Yield: 4.1 g (65.4%) Analysis (based on anhydrous compound): Calculated:C 64.64 H 9.28 N 5.03 Found: C 64.82 H 9.37 N 4.96

(b)3,6,9-Triaza-3,6,9-tris(carboxymethyl)-4-(4-butoxybenzyl)undecanedioicAcid

3.34 g (4 mmol) of the tert-butyl ester described in Example 9(a) isdissolved in 20 ml of trifluoroacetic acid, stirred for one hour at roomtemperature, and worked up analogously to Example 1(b).

Yield: 1.36 g (61.0%) Analysis (based on anhydrous material):Calculated: C 54.04 H 6.71 N 7.57 Found: C 53.88 H 6.63 N 7.41

(c) Disodium Salt of the Gadolinium Complex of3,6,9-Triaza-3,6,9-tris(carboxymethyl)-4-(4-butoxybenzyl)undecanedioicAcid

556 mg (1 mmol) of the complexing acid described in the precedingexample is combined with 40 ml of water and complexed at 80° C. with 181mg (0.5 mmol) of Gd₂ O₃. The mixture is then neutralized with 2 ml of 1NNaOH, stirred with activated carbon, filtered, and the filtratefreeze-dried.

Yield: 711 mg (94.3%) Analysis (based on anhydrous material):Calculated: C 39.83 H 4.28 Gd 20.86 N 5.58 Na 6.10 Found: C 39.61 H 4.35Gd 20.51 N 5.49 Na 6.17

The T₁ relaxation (1mmol·sec) is

in water 5.80±0.26

in plasma 14.20±0.98

Analogously, with the use of europium oxide, Eu₂ O₃, the correspondingeuropium complex is obtained:

Calculated: C 40.11 H 4.31 Eu 20.30 N 5.61 Na 6.14 Found: C 39.97 H 4.39Eu 20.02 N 5.72 Na 6.25

With iron oxide, Fe₂ O₃, the corresponding iron complex is analogouslyobtained:

Calculated: C 46.03 H 4.94 Fe 8.56 N 6.44 Na 7.05 Found: C 45.88 H 5.03Fe 8.30 N 6.50 Na 7.11

Example 10 (a)3,6,9-Triaza-3,6,9-tris(tert-butyoxcarbonylmethyl)-4-(4-benzyloxybenzyl)undecanedioicAcid Di-tert-butyl Diester

Analogously to Example 8(a), 5.85 g (7.5 mmol) of3,6,9-triaza-3,6,9-tris(tert-butyoxcarbonylmethyl)-4-(4-benzyloxybenzyl)undecanedioicacid di-tert-butyl diester (Example 9f of DOS 3,710,730) is reacted with1.71 g (10 mmol) of benzyl bromide and worked up as described therein.

Yield: 4.9 g (75.1%) Analysis (based on anhydrous substance):Calculated: C 66.25 H 8.69 N 4.83 Found: C 66.14 H 8.77 N 4.83

(b)3,6,9-Triaza-3,6,9-tris(carboxymethyl)-4-(4-benzyloxybenzyl)undecanedioicAcid

3.48 g (4 mmol) of the tert-butyl ester disclosed in Example 10(a) isdissolved in 20 ml of trifluoroacetic acid, stirred for one hour at roomtemperature, and worked up analogously to Example 1(b).

Yield: 1.33 g (56.5%) Analysis (based on anhydrous material):Calculated: C 57.04 H 5.98 N 7.13 Found: C 56.89 H 6.03 N 7.21

(c) Disodium Salt of the Gadolinium Complex of3,6,9-Triaza-3,6,9-tris(carboxymethyl)-4-(4-benzyloxybenzyl)undecanedioicAcid

590 mg (1 mmol) of the complexing acid described in the precedingexample is combined with 40 ml of water and 1 ml of 1N NaOH andcomplexed at 80° C. with 181 mg (0.5 mmol) of Gd₂ O₃. Then the mixtureis neutralized furthermore with 1 ml of 1N NaOH, stirred with activecarbon, filtered, and the filtrate freeze-dried.

Yield: 704 mg (89.2%) Analysis (based on anhydrous material):Calculated: C 42.69 H 3.84 Gd 19.96 N 5.33 Na 5.84 Found: C 42.63 H 3.91Gd 19.57 N 5.26 Na 5.99

The T₁ relaxation (1/mmol·sec) is

in water 5.81±0.11

in plasma 16.35±1.01

The corresponding europium complex is obtained analogously with europiumoxide, Eu₂ O₃ :

Calculated: C 42.98 H 3.86 Eu 19.42 N 5.37 Na 5.88 Found: C 43.10 H 3.91Eu 19.13 N 5.27 Na 5.99

With iron oxide, Fe₂ O₃, the corresponding iron complex is obtainedanalogously:

Calculated: C 48.99 H 4.41 Fe 8.14 N 6.12 Na 6.70 Found: C 48.73 H 4.57Fe 8.29 N 6.03 Na 6.85

Example 11 (a)4-Nitro-N-benzyloxycarbonyl-DL-phenylglycine-(2-aminoethyl)-amide-hydrochloride

588.5 g (3 mmol) of 4-nitro-DL-phenylglycine, produced according to J.Biochem. (Tokyo) 88(6), 1773, is suspended in 2.5 liters of ethanol.713.8 g (6 mol) of thionyl chloride is instilled under ice coolingwithin 90 minutes, refluxed for two hours, and the resulting solution isevaporated to dryness in a vacuum. The residue is dissolved in 5 litersof water, mixed with 5 liters of diethyl ether and brought to pH 8.5with 1.5 liters of a 1.5 m-sodium carbonate solution. Then, 511.8 g (3mol) of chloroformic acid benzyl ester and 1.8 liters of 1.5 m-sodiumcarbonate solution are instilled simultaneously with intensive stirring,so that the pH of the mixture is between 8.2 and 8.6. It is allowed tostir for two hours at room temperature, the organic phase is separated,it is washed neutral with water, dried on sodium sulfate and thefiltered solution is evaporated to dryness. The residue is dissolved in2 liters of methanol, and the solution is instilled slowly in 3.5 litersof ethylenediamine with intensive stirring. It is allowed to stir for 24hours, evaporated to dryness in a vacuum, the residue is dissolved in 2liters of hot methanol and the solution is mixed by instillation undercooling with conc. hydrochloric acid until permanent turbidity. It isallowed to crystallize in the ice bath for 24 hours, the precipitate issuctioned off, it is washed with a little ice-cold methanol and it isdried in a vacuum at 40° C.

1022.3 g (90% of theory) of the title compound is obtained as a yellowpowder with an uncharacteristic decomposition point.

    ______________________________________                                        Analysis:                                                                     ______________________________________                                        C     52.88    H     5.18   N   13.70  (calculated)                                 52.61          5.24       13.77  (found)                                ______________________________________                                    

b) 1.5-Diamino-3-aza-1-(4-nitrophenyl)-pentane

2.55.5 g (0.624 mol) of the compound obtained under a) is suspended in650 ml of a solution of hydrobromic acid in glacial acetic acid. It isallowed to stir for 30 minutes at room temperature and the solution ismixed with diethyl ether until permanent turbidity. After stirringovernight, the precipitated hydrobromide is suctioned off, dried anddissolved in 2 liters of water. After treatment with 1.25 liters ofAMBERLITE IRA 410 ion exchange material, the filtered solution isevaporated to dryness and dehydrated by codistillation with tolune. Theresidue is dissolved in 500 ml of tetrahydrofuran and again concentratedby evaporation. Then, 4.5 liters of a one-molar diborane-tetrahydrofurancomplex solution in tetrahydrofuran (ALDRICH) is added and reflexed for72 hours. After cooling off the solution, 500 ml of methanol iscarefully instilled and saturated under ice cooling with hydrochloricacid. It is allowed to stir for four more hours, the precipitate issuctioned off and dried in a vacuum after washing with tetrahydrofuranat room temperature. 170.9 g of the title compound is obtained astrihydrochloride of equivalent weight 113.4 (calculated: 111.2).

c)3,6,9-Triaza-3,6,9-tris(carboxymethyl)-4-(4-nitrophenyl)-undecanedioicacid

58.4 g (175 mmol) of the compound obtained under b) is dissolved in 630ml of water and 420 ml of a 10 molar potassium hydroxide solution, mixedwith 1.1 liters of tetrahydrofuran and, after the addition of 165.4 g(1.75 mol) of chloracetic acid, stirred for 72 hours at 50° C. It iscooled off to room temperature, the aqueous phase is separated,neutralized with conc. hydrochloric acid, and the solution is evaporatedto dryness in a vacuum. The residue is dehydrated by codistillation withtoluene, 2 liters of ethanol is added and 312.3 g of thionyl chloride isinstilled under ice cooling. It is refluxed for five hours, evaporatedto dryness in a vacuum and the residue is mixed with 2 liters of ethylacetate and 4 liters of a one-molar sodium bicarbonate solution. It isallowed to stir for two hours, the organic phase is separated, it iswashed with water, dried on sodium sulfate, filtered and evaporated todryness in a vacuum. The remaining yellow oil is the pentaethyl ester ofthe title compound. For samponification, 150 ml of tetrahydrofuran and150 ml (750 mmol) of 5n sodium hydroxide solution are added and allowedto stir for four hours at room temperature. The aqueous phase isseparated, filtered several times on activated carbon and acidified with50% by volume of sulfuric acid. It is allowed to stir for 24 hours in anice bath, the precipitate is suctioned off, it is washed with ice waterand dried in a vacuum at 50° C. 55.8 g (62% of theory) of the titlecompound is obtained as a white powder with a decomposition point above250° C.

    ______________________________________                                        Analysis:                                                                     ______________________________________                                        C     46.69    H     5.09   N   10.89  (calculated)                                 46.48          5.20       11.01  (found)                                ______________________________________                                    

d)3,6,9-Triaza-3,6,9-tris(carboxymethyl)-4-(hydroxyphenyl)-undecanedioicacid

51.4 g (0.1 mol) of the compound obtained under c) is suspended in 500ml of water and brought into solution by adding conc. sodium hydroxidesolution. The solution is mixed in an autoclave with 5 g ofpalladium-carbon catalyst (10% Pd) and saturated with hydrogen gas.After completion of the hydrogenation, it is suctioned off from thecatalyst, the solution is filtered on activated carbon and mixed with 15ml of glacial acetic acid. Then, a solution of 11 g (150 mmol) of sodiumnitrite in 50 ml of water and 50 ml of glacial acetic acid issimultaneously instilled in the ice bath with stirring, so that an innertemperature of 5° C. is not exceeded. It is allowed to stir for twohours at 5° C., then for two more hours at room temperature, 50 ml ofnitric acid (1:3) is added by instillation and heated for three hours to50° C. After cooling off and stirring in the ice bath overnight, theprecipitate is suctioned off, washed with water and recrystallized from90% ethanol. 29.1 g (60% of theory) of the title compound is obtained asa white powder with a decomposition point above 250° C.

    ______________________________________                                        Analysis:                                                                     ______________________________________                                        C       49.48      H     5.61     N   8.66                                            49.52            5.80         8.62                                    ______________________________________                                    

e)3,6,9-Triaza-3,6,9-tris(carboxymethyl)-4-(4ethoxyphenyl)-undecanedioicacid

4.85 g (10 mmol) of the compound obtained under d) is dissolved in 20 mlof dimethyl formamide. After cooling off in the ice bath, 300 mg (10mmol) of 80% sodium hydride and then 1.56 g (10 mmol) of iodine ethaneare carefully added for and allowed to stir at room temperatureovernight. It is heated for two hours to 40° C., 5 ml of water iscarefully instilled and the solution is evaporated to dryness in avacuum. The residue is stirred up with 100 ml of diethyl etherovernight, suctioned off and suspended in 20 ml of 2n hydrochloric acid.It is allowed to stir for one hour, again suctioned off, washed withwater and dried in a vacuum at 40° C., Several words illegible! titlecompound is obtained as a white powder with an uncharacteristicdecomposition point.

    ______________________________________                                        Analysis:                                                                     ______________________________________                                        C       51.46      H     6.08     N   8.18                                            51.33            6.17         8.13                                    ______________________________________                                    

f) Disodium salt of the gadolinium complex of3,6,9-triaza-3,6,9-tris(carboxymethyl)-4-(4-ethoxyphenyl)-undecanedioicacid

5.0 g of the compound obtained under e) is reacted in 30 ml of waterwith 1812 mg (5 mmol) of gadolinium oxide at 80° within one hour. Thesolution is ultrafiltered and freeze-dried. The title compound isobtained in quantitative yield with a gadolinium content of 22.1%(relative to the anhydrous substance.

Melting point: greater than 300° C.

Example 12

Analogously, as described in example 11, starting from2-amino-4-(4-nitrophenyl)-butyric acid, the complexes, according to theinvention, of3,6,9-triaza-3,6,9-tris(carboxymethyl)-4-(4-ethoxyphenylethyl)-undecanedioicacid are obtained.

Melting point: greater than 300° C.

Examples for in vivo NMR Diagnostics Example 1

Images were obtained at various times after administration of thedisodium salt of the gadolinium complex of Example 1(c) to rats with theaid of an NMR tomograph by General Electric, specifically developed foranimal experimental research.

Spin echo scans were made with the NMR tomograph (CSI 2 T) at 2 tesla(TR time of 400 ms and TE time of 20 ms). The layer thickness of this T₁-weighted imaging sequence was 3 mm; the image matrix was 128×128.

The contrast medium was administrated intravenously into a caudal veinof a male hairless rat (Lew/Mol) weighing 190 g, in a dose of 0.06mmol/kg. The animal had a Brown Pearce tumor in the thigh and wasanesthetized for the study by means of an intramuscular administrationof "Katavet"/"Rompun".

Various dark structures are visible in the abdomen in the coronary blankscan (baseline, No. 1). No differentiation was possible betweenintestinal lumen and stomach.

One minute after administration (No. 2), the first enhancement isalready apparent in the urinary bladder. A strong increase in contrastis visible in the stomach 45 minutes after injection (No. 3). A goodvisualization of the tumor (at the level of the reference tube), of theurinary bladder, and of the stomach can be observed 60 minutes afterinjection (No. 4). Moreover, contrasting of the intestine can likewisebe observed. This makes it possible to distinguish among intestinalloops, fat, as well as lymphatic nodes (lymphomas). Contrasting of therenal pelvis is also striking; this image can be even more improved 65minutes after injection in a somewhat different layer (No. 5). In FIG.6, 180 minutes after injection, the contrast enhancement is likewiseclearly recognizable in an axial scan in the zone of the liver. Thismakes it possible to differentiate among the stomach, the liver, theduodenum, and the pancreas.

Example 2

The test animals were female rats of the strain Lew/Mol weighing 160-180g. Prior to imaging, the animals were anesthetized ("Rompun"+"Ketavet")and provided with a catheter in the caudel vein to administer thecontrast medium. Imaging took place in an MRI experimental device byGeneral Electric (field strength 2 tesla). First of all, the images (7,9, 11) were made without contrast medium with a T₁ -weighted spin echosequence (TR=400 msec, TE=20 msec, axial section plane, layer thickness3 mm). The liver appears in each case with the normal signal intensity;the stomach is darker in tendency than the liver. In case of animal l,the stomach exhibits, in part, a rather high signal intensity. This isdue to feed residues, the feed containing manganese in relatively highconcentrations (at the time of the test, the animals had been fastingfor 6 hours). Animal 3 had been implanted with an osteogenic sarcomathree weeks previously; this sarcoma was of equal contrast in the blankimage and could not be defined. The administration of contrast mediumtook place via the venous catheter with a dose of 0.1 mmol Gd/kg(concentration of the solutions 0.05 mmol Gd/ml in 0.9% NaCl) for all 3compounds.

A marked enhancement of the liver can be found for all 3 compounds after90 minutes FIG. 8, Example 8(c)! and, respectively, after 60 minuteshave elapsed upon administration FIG. 10, Example 9(c); FIG. 12, Example10(c)!; this is due to uptake by the hepatocytes and cannot be observedat this point in time after administration with the contrast medium forNMR tomography, "Magnevist", heretofore the sole contrast mediumavailable on the market. In case of animal 3 FIG. 12, Example 10(c)!,the tumor is now additionally clearly visible, which has not absorbedthe contrast medium at all, or only to a lesser proportion.

Furthermore, all compounds--most strongly in case of Example 10(c),least in case of Example 8(c)--show great enhancement of the stomach.This offers additional diagnostic possibilities in view of an improveddistinction of liver and stomach.

The preceding examples can be repeated with similar success bysubstituting the generically or specifically described reactants and/oroperating conditions of this invention for those used in the precedingexamples.

From the foregoing description, one skilled in the art can easilyascertain the essential characteristics of this invention, and withoutdeparting from the spirit and scope thereof, can make various changesand modifications of the invention to adapt it to various usages andconditions.

What is claimed is:
 1. A compound of the formula ##STR4## wherein one ofZ¹ and Z² is H and the other is

    --(CH.sub.2).sub.m --(C.sub.6 H.sub.4).sub.q --(O).sub.k --(CH.sub.2).sub.n --(C.sub.6 H.sub.4).sub.l --(O).sub.r --R,

wherein m and n, independently, are each 0-20, k, l, q and r are each,independently, 0 or 1, R is H, C₁ -C₆ -alkyl, OR¹ -substituted C₁ -C₆-alkyl or CH₂ COOR¹, R¹ is H, C₁ -C₆ -alkyl or benzyl; and X is, in eachcase, a hydrogen atom or a metal ion equivalent of an element of atomicnumber 21-29, 42, 44 or 57-83;with the provisos that; at least two ofthe substituents X represent a metal ion equivalent; when n and l eachare 0, then k and r are not simultaneously 1; --(O)_(r) --R is not OH;Z¹ and Z² are not --CH₂ --C₆ H₄ --O--CH₂ --COOCH₂ C₆ H₅, --CH₂ --C₆ H₅,--CH₂ --C₆ H₄ --OCH₃ or --CH₂ --C₆ H₄ --O--(CH₂)₅ --COOCH₂ C₆ H₅ ; Z¹ isnot phenyl when Z² is H; and at least one of q and l is 1;or aphysiologically acceptable salt thereof with an inorganic and/or organicbase, an amino acid or amino acid amide.
 2. A compound of claim 1,wherein Z¹ is hydrogen and Z² is --(CH₂)_(m) --(C₆ H₄)_(q) --(O)_(k)--(CH₂)_(n) --(C₆ H₄)_(l) --(O)_(r) --R.
 3. A compound of claim 1,wherein Z² is hydrogen and Z² is --(CH₂)_(m) --(C₆ H₄)_(q) --(O)_(k)--(CH₂)_(n) --(C₆ H₄)_(l) --(O)_(r) --R.
 4. A compound of claim 1,wherein Z¹ is --CH₂ --C₆ H₄ --O--CH₂ --C₆ H₄ --OCH₃, --CH₂ O--CH₂ --C₆H₅, --CH₂ --C₆ H₄ --O--CH₂ --COOH, --CH₂ --C₆ H₄ --OC₂ H₅, --CH₂ --C₆ H₄--OC₄ H₉ or --CH₂ --C₆ H₄ --O--CH₂ --C₆ H₅.
 5. A compound of claim 1,wherein Z² is --CH₂ --C₆ H₄ --O--CH₂ --C₆ H₄ --OCH₃, --CH₂ O--CH₂ --C₆H₅, --CH₂ --C₆ H₄ --O--CH₂ --COOH, --CH₂ --C₆ H₄ --OC₂ H₅, --CH₂ --C₆ H₄H₉ or --CH₂ --C₆ H₄ --O--CH₂ --C₆ H₅.
 6. A compound of claim 1, whereinat least three X groups represent a Gd ion.
 7. A compound of claim 4,wherein at least three X groups represent a Gd ion.
 8. A compound ofclaim 5, wherein at least three X groups represent a Gd ion.
 9. Acompound of claim 1, wherein said compound is:gadolinium complex of3,6,9-triaza-3,6,9-triaza-3,6,9-tris(carboxymethyl)-4-4-(4-methoxybenzyloxy)benzyl!undecadenioic acid or a physiologicallyacceptable salt thereof; gadolinium complex of3,6,9-triaza-3,6,9-tris(carboxymethyl-4-benzyloxymethylundecanedioicacid or a physiologically acceptable salt thereof; gadolinium complex of3,6,9-triaza-3,6,9-tris(carboxymethyl-4-carboxymethoxybenzyl)undecanedioicacid or a physiologically acceptable salt thereof; gadolinium complex of3,6,9-triaza-3,6,9-tris(carboxymethyl-4-ethoxybenzyl)undecanedioic acidor a physiologically acceptable salt thereof; europium complex of3,6,9-triaza-3,6,9-tris(carboxymethyl)-4-(4-ethoxybenzyl)undecanedioicacid or a physiologically acceptable salt thereof; iron complex of3,6,9-triaza-3,6,9-tris(carboxymethyl)-4-(4-ethoxybenzyl)undecanedioicacid or a physiologically acceptable salt thereof; gadolinium complex of3,6,9-triaza-3,6,9-tris(carboxymethyl-4-butoxybenzyl)undecanedioic acidor a physiologically acceptable salt thereof; europium complex of3,6,9-triaza-3,6,9-tris(carboxymethyl)-4-(4-butoxybenzyl)undecanedioicacid or a physiologically acceptable salt thereof; iron complex of3,6,9-triaza-3,6,9-tris(carboxymethyl)-4-(4-butoxybenzyl)undecanedioicacid or a physiologically acceptable salt thereof; gadolinium complex of3,6,9-triaza-3,6,9-tris(carboxymethyl-4-(4-benzyloxybenzyl)undecanedioicacid or a physiologically acceptable salt thereof; europium complex of3,6,9-triaza-3,6,9-tris(carboxymethyl)-4-(4-benzyloxybenzyl)undecanedioicacid or a physiologically acceptable salt thereof; or iron complex of3,6,9-triaza-3,6,9-tris(carboxymethyl)-4-(4-benzyloxybenzyl)undecanedioicacid or a physiologically acceptable salt thereof.
 10. A pharmaceuticalcomposition comprising a compound of claim 1 and a pharmaceuticalacceptable carrier.
 11. In a method of NMR imaging a patient comprisingadministering an NMR contrast agent to said patient, the improvementwherein:said contrast agent exhibits both renal and extrarenalexcretion, and said contrast agent provides enhanced contrast of therenal system, the gastrointestinal tract and the liver, gall bladder,and bile ducts.
 12. A compound according to claim 1, wherein at leasttwo of the X groups represent a metal ion of atomic number 21-29, 42, 44or 58-70.
 13. A compound according to claim 1, wherein two of the Xgroups represent manganese(II), iron(II), cobalt(II) or copper(II); orthree of the X groups represent chromium(III), praseodymium(III),neodymium(III), samarium(III), ytterbium(III), gadolinium(III),terbium(III), dysprosium(III), holmium(III), erbium(III), or iron(III).14. A compound according to claim 1, wherein Z¹ is --C₆ H₄ --O--C₂ H₅ or--C₂ H₄ --C₆ H₄ --O--C₂ H₅.
 15. A compound according to claim 1, whereinsaid compound is gadolinium complex of3,6,9-triaza-3,6,9-tris(carboxymethyl)-4-(4-ethoxyphenyl)undecanedioicacid or a physiologically acceptable salt thereof.
 16. A compoundaccording to claim 1, wherein said compound is a complex of3,6,9-triaza-3,6,9-tris(carboxymethyl)-4-(4ethoxyphenylethyl)undecanedioicacid and a metal ion of atomic number 21-29, 42, 44 or 57-83, or aphysiologically acceptable salt thereof.
 17. A compound according toclaim 1, wherein R is C₁₋₆ -alkyl or C₁₋₆ -alkyl substituted by --OR¹.18. A compound according to claim 1, wherein one of Z¹ and Z² is --CH₂--C₆ H₄ --O--(CH₂)_(n) --(C₆ H₄)₁ --(O)_(r) --R.
 19. A compoundaccording to claim 1, wherein one of Z¹ and Z² is --(CH₂)_(m) --C₆ H₄--O--CH₂ --C₆ H₄ --(O)_(r) --R.
 20. A compound according to claim 1,wherein the X groups which do not represent a metal ion equivalent ofatomic number 21-29, 42, 44 or 57-83 are individually lithium, potassiumor sodium, or two such X groups are calcium or magnesium.
 21. A compoundaccording to claim 1, wherein the groups which are not a metal ionequivalent of an element of atomic number 21-29, 42, 44 or 57-83represent a salt with ethanolamine, diethanolamine, morpholine,glucamine, N,N-dimethylglucamine, N-methylglucamine, lysine, arginine,ornithine, lysine methylamide, glycine ethylamide or serine methylamide.22. A composition according to claim 10, wherein the amount of saidcompound is 50 μmol/l-2 mol/l.
 23. A composition according to claim 10,wherein the amount of said compound is 100 mmol/l-1 mol/l.
 24. Acompound of claim 4, wherein Z¹ is --CH₂ --C₆ H₄ --O--CH₂ --C₆ H₄--OCH₃, --CH₂ --O--CH₂ --C₆ H₅ or --CH₂ --C₆ H₄ O--CH₂ --COOH.
 25. Acompound of claim 4, wherein Z² is --CH₂ --C₆ H₄ --O--CH₂ --C₆ H₄--OCH₃, --CH₂ --O--CH₂ --C₆ H₅ or --CH₂ --C₆ H₄ O--CH₂ --COOH.
 26. Acompound according to claim 14, wherein Z² is --C₆ H₄ --OC₂ H₅.
 27. Acompound according to claim 1, wherein Z¹ is --C₆ H₄ --OC₂ H₅ or --C₂ H₄--C₆ H₅ OC₂ H₅.
 28. A compound according to claim 26, wherein two of theX groups represent manganese(II), iron(II), cobalt(II), or copper(II);or three of the X groups represent chromium(III), praseodymium(III),neodmium(III), samarium(III), ytterbium(III), gadolinium(III)terbium(III), dysprosium(III), holmium(III), erbium(III), or iron(III).29. A compound according to claim 10, wherein said composition furthercomprises at least one physiologically acceptable buffer, at least onecomplexing agent, at least one electrolyte, and/or at least oneantioxidant.
 30. A compound according to claim 10, wherein said carrieris an aqueous medium and said composition contains 50 μmol/l-2 mol/l ofsaid compound.
 31. A compound according to claim 10, wherein saidcarrier is an aqueous medium and said composition contains 100 mmol/l-1mol/l of said compound.
 32. A method according to claim 11, wherein saidNMR contrast agent is administered intravenously.
 33. A method accordingto claim 11, wherein said NMR contrast agent is administered in a doseof 1 μmol/kg-5 mmol/kg.
 34. A method according to claim 11, wherein saidNMR contrast agent is administered in a dose of 10 μmol/kg-0.5 mmol/kg.35. In a method of conducting radiation therapy of a patient comprisingadministering a radioactive metal ion to the patient, the improvementwherein the radioactive metal ion is administered in the form of acompound of claim 1.